Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution
Menée à l'aide d'un outil numérique permettant d'identifier une perte d'hétérozygotie des antigènes des leucocytes humains (HLA) dans des données de séquençage, cette étude montre notamment que la perte d'hétérozygotie du locus HLA survient dans 40% des cancers du poumon non à petites cellules et que ce mécanisme d'échappement au système immunitaire est soumis à une forte pression de sélection par le microenvironnement de façon tardive dans l'évolution d'une tumeur
Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens.
Cell 2017